Tenofovir granules

ABSTRACT

The present invention relates to a granular composition comprising essentially Tenofovir, wherein the composition is devoid of an excipient. Tenofovir granules of the present invention are prepared in twin-screw processor such that the content of total impurities in the prepared granules is less than 2.0%.

This application is a continuation of U.S. application Ser. No.15/881,413, filed Jan. 26, 2018, which claims benefit of Serial No.201741003161, filed 27 Jan. 2017 in India and is incorporated herein byreference. To the extent appropriate, a claim of priority is made to theabove disclosed application.

FIELD OF THE INVENTION

The present invention relates to a granular composition consistingessentially of Tenofovir, wherein the composition is devoid of anexcipient.

BACKGROUND OF THE INVENTION

Tenofovir, is chemically, 9-[2-(R)-(phosphonomethoxy) propyl] adenine(PMPA). Tenofovir disoproxil is a pro-drug of Tenofovir. It hasincreased oral bioavailability compared to Tenofovir. Tenofovir isapproved for commercial use as in the form of Tenofovir disoproxilfumarate (TDF), chemically known as9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl] methoxy]propyl] adenine fumarate (1:1).

Tenofovir Disoproxil Fumarate 300 mg Tablets are indicated incombination with other anti-retrovirals for the treatment of HIV-1infection in adults and adolescents aged over 12 years. TenofovirDisoproxil Fumarate 300 mg Tablets are indicated for the treatment ofchronic hepatitis B in adults and adolescents aged over 12 years withcompensated liver disease, with evidence of active viral replication,persistently elevated serum alanine aminotransferase (ALT) levels andhistological evidence of active inflammation and/or fibrosis.

Tenofovir disoproxil fumarate (TDF) is observed to have poor flowproperties, therefore aqueous or non-aqueous wet granulation is apreferred processing step in the formulation of the TDF tablets, by mostpharmaceutical manufacturers. Also, as per International Journal of DrugDevelopment & Research, 2012, Volume 4, Issue 1, Pages 247-256; forEmtricitabine and Tenofovir disoproxil fumarate film coated tablets, wetgranulation with pregelatinized starch as binder was found to be thebest method of choice for formulation of these tablets, as compared todirect compression.

Literature is also available on non-wet granulation techniques forcompounding Tenofovir. For example—EP 2389929A1 discloses compositionsof Tenofovir with pregelatinized starch (5-15%) by weight prepared bydirect compression. IN 2621/CHE/2013 discloses a hot-melt extrudedTenofovir disoproxil composition having a binder. 843/CHE/2013 disclosesan extrusion-spheronization process for preparation of oralmulti-particulate compositions composed of Tenofovir coated with ethylcellulose or methacrylic acid co-polymers. CN103330683 B discloseshot-melt extrusion of Tenofovir disoproxil fumarate with sweetener andpolymer Kollidon® VA64, Kollicoat® IR andSoluplus® to prepare finegranules. European Patent Document EP1890681 B1 describes a methodcomprising dry granulating a composition comprising a pharmaceuticallyacceptable excipient, emtricitabine and tenofovir DF to produce drygranules.

However, none of the references suggest or disclose free flowingdirectly compressible Tenofovir granules devoid of an excipient, or aprocess for preparation of such granules. Such granules would bespecifically more advantageous in case of unit dose antiretroviral oralfixed dose combinations where there is a larger percentage of API in thefinished dosage form. For example—Atripla® tablets, Complera® tablets,Stribild® tablets, Emtricitabine200 mg/Tenofovir disoproxil fumarate 300mg+Nevirapine 200 mg tablets, etc. Besides, since TDF is sensitivetowards hydrolytic degradation. It would be highly desirable to processTDF in conditions which can prevent or minimize such hydrolyticdegradation. Further, it would be most desirable to prepare free flowingdirectly compressible Tenofovir granules devoid of an excipient whichcan remain stable at 40° C. and 75% relative humidity for three months.

As per, Authorized USP Pending Monograph Version 1; following are theimpurities known for Tenofovir Disoproxil Fumarate—

-   Tenofovir isoproxil monoester—({[(R)-1-(6-Amino-9H-purin-9-yl)    propan-2-yloxy] methyl} (hydroxy) phosphoryloxy) methyl isopropyl    carbonate-   Tenofovir isopropyl    isoproxil—O-(Isopropoxycarbonyloxymethyl)-O-isopropyl-{(R)-[1-(6-amino-9H-purin-9-yl)    propan-2-yloxy]}methylphosphonate-   Tenofovir disoproxil ethyl    ester—O-(Ethoxycarbonyloxymethyl)-O-(isopropoxycarbonyloxymethyl)-{(R)-[1-(6-amino-9H-purin-9-yl)    propan-2-yloxy]}methylphosphonate-   Tenofovir disoproxil carbamate—O, O-Bis (isopropoxycarbonyl    oxymethyl){(R)-1-[(6-isopropoxycarbonylamino)-9H-purin-9yl]    propan-2-yloxy]}methylphosphonate and-   Tenofovir disoproxil dimer—Tetra(isopropoxycarbonyloxymethyl)    (2S)-1,1′-[6,6′-methylenebis(azanediyl)bis(9H-purine-9,6-diyl)]bis(propane-2,1-diyl)bis(oxy)bis(methylene)diphosphonate.

In view of increasing demand for Tenofovir products, sources ofquality-assured Tenofovir are constantly needed for the production ofgood-quality finished dosage forms. Also, TDF API (Active PharmaceuticalIngredient) or dosage forms, with tighter specifications for impuritieswould be highly desirable.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a granular compositionconsisting essentially of Tenofovir, wherein the composition is devoidof an excipient.

It is an object of the invention to provide a granular compositionconsisting essentially of Tenofovir, wherein the total impurities arenot more than 2.0%.

It is another object of the invention to provide a process forpreparation of a granular composition consisting of Tenofovir, devoid ofan excipient, using a twin-screw processor.

It is another object of the invention to provide a tablet comprising i)the granular composition of Tenofovir prepared in twin screw processorhaving a content of total impurities of not more than 2.0% and ii) oneor more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

According to an aspect of the present invention, there is provided aprocess for preparing a granular composition of Tenofovir in a twinscrew processor comprising the steps of

-   -   a. feeding Tenofovir into the intake zone of the twin screw        processor;    -   b. conveying Tenofovir towards the kneading zone and processing        it in the kneading zone;    -   c. conveying Tenofovir from the kneading zone towards the exit;    -   d. collecting the Tenofovir granules; and wherein the        temperature of the barrel is between 25° C. and 60° C.,    -   wherein the granules are devoid of an excipient.

According to another aspect of the present invention, there is provideda granular composition consisting essentially of Tenofovir, wherein thecomposition is devoid of an excipient and the content of totalimpurities is not more than 2.0%.

According to yet another aspect of the present invention there isprovided a tablet comprising a) the granular composition of Tenofovirprepared in a twin screw processor having a content of total impuritiesof not more than 2.0% and b) one or more pharmaceutically acceptableexcipients.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: DSC thermogram for TDF granules as per Example 5.

FIG. 2: DSC of TDF API before feeding into twin screw processor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing a granularcomposition consisting essentially of Tenofovir, wherein the compositionis devoid of an excipient.

Unless otherwise mentioned, the term “Tenofovir” as used herein,includes Tenofovir and pharmaceutically acceptable salts, esters,prodrugs or derivatives; or salts of said esters or prodrugs orderivatives, thereof. Tenofovir disoproxil fumarate is the preferredsalt, which is the reason for describing the invention with reference toTenofovir disoproxil fumarate, although it must not be considered to belimited only to the use of Tenofovir disoproxil fumarate.

The term “excipient” as used herein means substances used to formulateTenofovir into pharmaceutical compositions. It also includes diluents,disintegrants, solubilizers, stabilizers, surfactants, binders,polymers, flow promoters, granulation aids and lubricants.

Unless otherwise mentioned, the term “consisting of” when used inconnection with tenofovir means tenofovir inclusive of the known andunknown impurities as described in this specification.

In accordance with an embodiment, the present invention provides agranular composition consisting essentially of Tenofovir, wherein thecomposition is devoid of an excipient.

Such a composition can be directly compressed after mixing with one ormore, pharmaceutically acceptable excipients, and is suitable forpreparation of oral solid dosage forms, such as tablets. An excipientsuch as pregelatinized starch is not required as a pharmaceuticallyacceptable excipient for direct compression. The granular Tenofovircomposition devoid of an excipient, itself has good compressibility andflow properties. Particularly, no additional excipients are required toprepare Tenofovir granules. This has more significance, in case of fixeddose combinations of Tenofovir with other anti-retrovirals, as unitdosage forms, wherein it can aid reduction in size of the unit dosageform. Some of the examples of other anti-retroviral active moieties ortheir pharmaceutically acceptable derivatives/analogues or other activepharmaceutical ingredient/s, that can be incorporated into such a fixeddose combination with Tenofovir are-Efavirenz, Emtricitabine,Rilpivirine, Lamivudine, Nevirapine, Elvitegravir, Dolutegravir andCobicistat.

In accordance with a further embodiment, the granular Tenofovircomposition devoid of an excipient, has a compressibility index of lessthan 30.

In accordance with an embodiment, the granular composition consistingessentially of Tenofovir can be prepared by twin screw granulation. Twinscrew granulation refers to the process of granulation carried out in atwin-screw processor.

In accordance with an embodiment, the present invention provides aprocess for preparation of a granular composition consisting ofTenofovir, devoid of an excipient, using a twin-screw processor.

A co-rotating twin screw processor is used in one of the embodiments, toprepare the said granular composition of Tenofovir. The co-rotatingtwin-screw processor has two co-rotating screws inside a processorbarrel. The processor barrel has barrel sections which are provided withtemperature control means. These screws are open length wise, and closedcross wise. The co-rotating twin screw processor has a modular designfor barrels and screws. Segmented screws convey and shear the materialsin channels bound by screw flights and barrel walls, with short masstransfer distances. Each individual screw section is designed to performspecific functions such as conveying, mixing, shearing, or pressurebuilding, thus allowing precise control of conditions along the screwlength. The screw elements differ in pitch, pitch direction, length, andangle of offset. Pitch, length, and location of such screw elements onthe shaft define a screw profile that influences the productcharacteristics. Due to variable screw configuration, the twin screwprocessor provides greater flexibility of operations to controlcharacteristics of product by monitoring and regulating residence time,product temperature, pressure, and shear.

Alternatively, suitable extruders can also be used without a die at theexit. The barrel temperatures would depend on the kind of extruder orthe kind of screw configuration within the extruder that is used.

During twin screw granulation process of Tenofovir disoproxil fumarate,in the co-rotating twin screw processor, the barrel temperature/s, screwspeed and feed rate are adjusted such, that the following impurities orrelated substances known for Tenofovir disoproxil fumarate, viz.—

-   Tenofovir isoproxil monoester—({[(R)-1-(6-Amino-9H-purin-9-yl)    propan-2-yloxy] methyl} (hydroxy) phosphoryloxy) methyl isopropyl    carbonate,-   Tenofovir isopropyl    isoproxil—O-(Isopropoxycarbonyloxymethyl)-O-isopropyl-{(R)-[1-(6-amino-9H-purin-9-yl)    propan-2-yloxy]}methylphosphonate,-   Tenofovir disoproxil ethyl    ester-O-(Ethoxycarbonyloxymethyl)-O-(isopropoxycarbonyloxymethyl)-{(R)-[1-(6-amino-9H-purin-9-yl)    propan-2-yloxy]}methylphosphonate,-   Tenofovir disoproxil carbamate—O, O-Bis (isopropoxycarbonyl    oxymethyl){(R)-1-[(6-isopropoxycarbonylamino)-9H-purin-9yl]    propan-2-yloxy]}methylphosphonate, and-   Tenofovir disoproxil dimer—Tetra(isopropoxycarbonyloxymethyl)    (2S)-1,1′-[6,6′-methylenebis(azanediyl)bis(9H-purine-9,6-diyl)]bis(propane-2,1-diyl)bis(oxy)bis(methylene)diphosphonate,

are not increased, or increase minimally, after granulating TDF throughthe twin screw processor.

Such a process is simple and involves feeding of TDF into theco-rotating twin screw processor and collection of free flowing directlycompressible (DC) TDF granules. The TDF API was fed into a barrelsection and was transferred forward along the screw length through theother barrel sections towards the exit port where the TDF granules werecollected. The barrel temperature profile can be maintained using thetemperature control means provided separately to different barrelsections. The temperatures can be as low as about 25° C. and as high asabout 60° C. All the barrel sections can also be maintained at the sametemperature, if desired. However, the barrel temperatures to bemaintained depend on the residence time of TDF in the processor, whichin turn depends on the screw speed. These variables can be adjusted toobtain desired quality of TDF granules. The granules can be fed into thetwin screw processor by means of specially designed feeders to increasethe feed rate.

The twin screw processor enables to prepare a product with even tighterspecifications for impurity levels and with an improvement in thecompressibility of Tenofovir API.

The twin screw processor enables to prepare a product with minimalincrease in impurity levels as compared to the input API. The product soobtained is granular and remains stable even under accelerated stabilityconditions. The granular compositions of Tenofovir packed in aluminiumpouches of 20 micron thickness were found to remain stable.

In accordance with a further embodiment, there is provided a granularTenofovir composition devoid of an excipient comprising Tenofovir, notmore than 1% Tenofovir isoproxil monoester and not more than 0.15%Tenofovir disoproxil dimer.

In accordance with a further embodiment, there is provided a granularTenofovir composition comprising Tenofovir, not more than 1% Tenofovirisoproxil monoester and not more than 0.15% Tenofovir disoproxil dimerafter storage at 40° C. and 75% Relative Humidity for a period of atleast 3 months; wherein the composition is devoid of an excipient.

In accordance with a further embodiment, there is provided a granularTenofovir composition comprising Tenofovir, not more than 1% Tenofovirisoproxil monoester and not more than 0.15% Tenofovir disoproxil dimerafter storage at 25° C. and 60% Relative Humidity for a period of atleast 3 months; wherein the composition is devoid of an excipient.

In accordance with a further embodiment, there is provided a granularTenofovir composition comprising Tenofovir, not more than 1% Tenofovirisoproxil monoester and not more than 0.15% Tenofovir disoproxil dimerafter storage at 2-8° C. for a period of at least 3 months; wherein thecomposition is devoid of an excipient.

In accordance with a further embodiment, there is provided a granularTenofovir composition comprising Tenofovir, not more than 0.15% adenine,not more than 1% Tenofovir isoproxil monoester, not more than 0.15%Tenofovir disoproxil ethylester, not more than 0.3% Tenofovir isopropylisoproxil, not more than 0.15% Tenofovir disoproxil carbamate, not morethan 0.15% Tenofovir disoproxil dimer, not more than 0.10% of anyindividual unspecified impurity and not more than 2.0% of totalimpurities; wherein the composition is devoid of an excipient.

In accordance with a further embodiment, there is provided a granularTenofovir composition comprising Tenofovir, not more than 1% Tenofovirisoproxil monoester and not more than 0.15% Tenofovir disoproxil dimer,prepared by a twin-screw granulation process; wherein the composition isdevoid of an excipient.

In accordance with a further embodiment, there is provided a granularTenofovir composition comprising Tenofovir, not more than 0.15% adenine,not more than 1% Tenofovir isoproxil monoester, not more than 0.15%Tenofovir disoproxil ethyl ester, not more than 0.3% Tenofovir isopropylisoproxil, not more than 0.15% Tenofovir disoproxil carbamate, not morethan 0.15% Tenofovir disoproxil dimer, not more than 0.10% of anyindividual unspecified impurity and not more than 2.0% of totalimpurities, prepared by a twin screw granulation process; wherein thecomposition is devoid of an excipient.

In accordance with the primary embodiment of the present invention,there is provided a process for preparing granular composition ofTenofovir in twin screw processor comprising the steps of

-   -   a. feeding Tenofovir into the intake zone of the twin screw        processor;    -   b. conveying Tenofovir towards the kneading zone and processing        it in the kneading zone;    -   c. conveying Tenofovir from the kneading zone towards the exit;    -   d. collecting the Tenofovir granules; and wherein the        temperature of the barrel is between 25° C. and 60° C.,    -   wherein the granules are devoid of an excipient.

In accordance with another embodiment, of the present invention, thereis provided a process for preparing tablets comprising Tenofovir, theprocess comprising the steps of: (a) twin screw granulation of Tenofovirwithout an excipient to form granules; (b) optionally, sieving theTenofovir granules; (c) optionally, adding one or more excipients to themixture; (e) compressing the resulting mixture into tablets.

In accordance with an embodiment of the present invention, the contentof Tenofovir in solid oral composition is 200 to 400 mg, more preferably300 mg. In an embodiment of the present, there is provided a tabletcomprising a) the granular composition of Tenofovir prepared in the twinscrew processor having content of total impurities of not more than 2.0%and b) one or more pharmaceutically acceptable excipients.

Similarly, the Tenofovir granules can be formulated with otheranti-retrovirals or other active pharmaceutical ingredient/s in the formof granules or powders or tablets.

The invention is described by the following non-limiting examples.

EXAMPLES Example 1

Granules of Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (TDF) was fed into an OMICRON 10Pprocessor in barrel section B1, STEER ENGINEERING PVT. LTD., Do/Di=1.71and processed at Screw Speed300 rpm, Barrel Temperature 25° C. and feedrate of 5.0 g/minute.

The screw configuration was as follows:

TABLE 1 Screw configuration for OMICRON 10P RSE RSE RSE RKB NKB RSE RSEElements 10/10 20/20 10/10 45/5/10 90/5/10 20/20 10/10 Number 1 3 5 2 23 2onsB1/B2/B3/B4 were kept at 25° C. TDF Granules were collected afterexiting barrel section B4.

Following were the granule properties:

TABLE 2 Granule properties for TDF granules of Example 1 Mesh No. %Cumulative wt. retained #20 (850 μm) 13.03 #40 (450 μm) 40.56 #60 (250μm) 61.21 #100 (150 μm) 73.58 Mean Particle Diameter 350 μm

Bulk Density (g/cc)—0.542, Tapped Density (g/cc)—0.766, CompressibilityIndex (%)—29.268, Hausner Ratio-1.414

Analytical Testing Organic Impurities for Tenofovir Granules

The test of organic impurities of Tenofovir Disoproxil Fumarate granulescarried out by HPLC (Make-Agilent 1260 Infinity series).

The Tenofovir Disoproxil Fumarate granules sample was analyzed fororganic impurities as per method based on Organic impurities, procedure1 of USP Pending Monographs of Tenofovir Disoproxil Fumarate v.1Authorized Sep. 1, 2011.

The standard, Tenofovir Disoproxil Fumarate (TDF) was prepared insolution A. concentration 0.502 μg/mL in solution. The sample i.e., TDFgranules of the present invention was prepared in solution A,concentration 520.05 μg/mL.

The standard and sample solution was injected in chromatographic systemand following impurity results are reported.

TABLE 3 Comparative results of analytical testing for TDF granules ofExample 1: Unprocessed Example 1 Acceptance Impurity TDF API (%) (%)criteria (%) Adenine Not Not NMT 0.15 detected detectedTenofovirisoproxil 0.48 0.50 NMT 1.0 monoester Tenofovirdisoproxil 0.030.03 NMT 0.15 ethyl ester Tenofovir isopropyl 0.17 0.18 NMT 0.30isoproxil Tenofovirdisoproxil Not Not NMT 0.15 carbamate detecteddetected Tenofovirdisoproxil 0.04 0.07 NMT 0.15 dimer Any individual0.02 0.02 NMT 0.10 unspecified impurity Total impurities 0.84 0.90 NMT2.0 NMT = Not More Than

Observation

From above impurity data, it is apparent that after granulation of TDF,the impurity Tenofovir isoproxil monoester is less than 1.00% andimpurity Tenofovir disoproxil dimer is less than 0.15%. Also, the totalimpurities are less than 1.0%

Preparation of Tablets from Granules of Example 1

The TDF granules of example 1 were compressed using 11 mm standard diepunch set.

Quantitative Composition for Unit Dose Tablet

TABLE 4 Quantitative composition for Tenofovir tablet IngredientsQuantity (mg) Tenofovir disoproxil fumarate 300 mg granules of Example 1Microcrystalline cellulose 125 mg Croscarmellose Sodium 15 mg MagnesiumStearate 5 mg Fumed silica 5 mg Total weight 450 mg

Tablet Characteristics—

Hardness—7-9 kp, Thickness—5.55 mm, % Friability—0.322, Disintegrationtime—25-30 seconds

Examples 2 to 4: Granules of Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate was fed into an OMICRON 10P processor inbarrel section B1, STEER ENGINEERING PVT. LTD., Do/Di=1.71 and processedat the following processing conditions

TABLE 5 Processing conditions for Examples 2-4: Barrel temperature ScrewFeed profile (° C.) Examples speed RPM rate g/min B1/B2/B3/B4 Example 2300 5.0 25/40/25/25 Example3 300 5.0 25/40/40/25 Example4 300 5.025/60/25/25

The screw configuration was same as that for Example 1. TDF Granuleswere collected after exiting barrel section B4.

Tenofovir granules of Examples 2, 3 and 4 were given for analysis: Theresults are as follows:

TABLE 6 Comparative results of analytical testing for TDF granules ofExamples 2-4 Unprocessed Acceptance Impurities TDF API Example2 Example3Example 4 criteriain % Adenine Not Not Not Not NMT 0.15 detecteddetected detected detected Tenofovir isoproxil 0.48 0.52 0.51 0.49 NMT1.0 monoester Tenofovir 0.03 0.03 0.03 0.03 NMT 0.15 disoproxilethylester Tenofovir 0.17 0.17 0.17 0.17 NMT 0.30 isopropylisoproxylTenofovir Not Not Not Not NMT 0.15 disoproxil detected detected detecteddetected carbamate Tenofovir 0.04 0.08 0.11 0.07 NMT 0.15 disoproxildimer Any individual 0.02 0.03 0.03 0.02 NMT 0.10 Unspecified impurityTotal 0.84 0.92 0.94 0.92 NMT 2.0 impurities

Example 5

Tenofovir disoproxil fumarate (TDF) was fed into an OMICRON 10Pprocessor in barrel section B1, STEER ENGINEERING PVT. LTD., Do/Di=1.71and processed at Screw Speed300 rpm, Barrel Temperature 25° C. and feedrate of 5.0 g/minute. The screw configuration was same as that forExample 1.

All barrel sections B1/B2/B3/B4 were kept at 25° C.TDF Granules werecollected after exiting barrel section B4.

Thermal Analysis:

After granulating, the TDF granules were analyzed using DSC. The meltingproperties obtained from DSC thermogram, were recorded with a DSCinstrument (DSC Q200, TA instrument). The DSC Q200 instrument wascalibrated for temperature and enthalpy with indium as a certifiedreference material (m.p.=156.6° C.; Enthalpy of fusion=3.296 (kJ/mol)2.Samples of TDF granules were sealed in standard aluminium pans andheated in the DSC from 25° C. to 250° C., at a heating rate of 5°C./minute. Dry N₂ gas, at a flow rate of 50 ml/min, was used to purgethe DSC equipment during measurement. The melting point of TDF granulesas per example 5 was 117.65° C.

Example 6

Tenofovir disoproxil fumarate was fed into an OMICRON 10P processor,STEER ENGINEERING PVT. LTD., Do/Di=1.71 and processed at Screw Speed 300rpm, Barrel Temperature 25° C. and feed rate same as Example 1.

The screw configuration was the same as Example 1:

TABLE 7 Screw configuration for OMICRON 10P RSE RSE RSE RKB NKB RSE RSEElements 10/10 20/20 10/10 45/5/10 90/5/10 20/20 10/10 Number 1 3 5 2 23 2 Zones Feeding and Kneading zone Conveying metering zone zoneAll barrels B1/B2/B3/B4 were kept at 25° C. as in Example 1. TDFGranules were collected after exiting barrel section B4.

Following were the granule properties:

TABLE 8 Granule properties for TDF granules of Example 6 Mesh No. %Cumulative wt. retained #20 (850 μm) 10.58 #40 (450 μm) 38.12 #60 (250μm) 56.45 #100 (150 μm) 70.49 Mean Particle Diameter 300

Bulk Density (g/cc)—0.550, Tapped Density (g/cc)—0.748, CompressibilityIndex (%)—26.47, Hausner's Ratio—1.36

Stability Testing:

The granules were loaded for stability at the following stabilityconditions for up to 3 months.

-   -   1. 2-8° C.    -   2. 25° C. and 60% Relative Humidity    -   3. 40° C. and 75% Relative Humidity

Samples were withdrawn at each month and Impurity testing (for relatedsubstances) was performed.

Analytical Testing Organic Impurities for Tenofovir Granules

The test of organic impurities of Tenofovir Disoproxil Fumarate granulescarried out by HPLC (Agilent 1260 Infinity series).

The Tenofovir Disoproxil Fumarate granules sample were analyzed fororganic impurities as per Organic impurities, procedure 1 of USP PendingMonographs of Tenofovir Disoproxil Fumarate v.1 Authorized Sep. 1, 2011.

The standard [Tenofovir Disoproxil Fumarate (TDF)] was prepared insolution A. concentration 0.502 μg/mL in solution.

The sample [TDF granules of the present invention] was prepared insolution A, concentration 520.05 μg/mL.

The standard and sample solution was injected in chromatographic systemand following impurity results are reported.

TABLE 9 Comparative results of analytical testing for TDF granules ofExample 6 Acceptance Level (%) of the Present Criteria Invention (NMT %)Tenofovir Stability data USP DC (3M) Pending Grade 25° C./ 40° C./Monograph Unprocessed Granules 2- 60% 75% Name of Impurity API Tablets(API) initial (Initial) 8° C. RH RH (R)-9-(2- 0.15 0.2 BDL BDL BDL BDLBDL Phosphono- methoxypropyl) adenine Adenine 0.15 0.2 BDL BDL BDL BDLBDL Tenofovirisoproxil 1.0 3.0 0.321 0.355 0.420 0.555 0.766 monoesterTenofovirdisoproxil 0.15 — ND ND ND ND ND ethyl ester Tenofovirisopropyl 0.3 — 0.118 0.120 0.132 0.126 0.123 isoproxil Tenofovir 0.25 —ND ND ND ND ND disoproxil Carbamate Tenofovirdisoproxil 0.15 0.75 ND NDND ND ND dimer Any individual 0.1 0.2 0.015 0.036 0.055 0.068 0.263unknown impurity Total impurity 2.0 4.0 0.490 0.584 0.661 0.874 1.555

List of Abbreviations

NMT—Not More Than

BDL—Below Detection Limit

ND—Not Detected

RH—Relative Humidity

Observation

From above impurity data, it is apparent that after granulation of TDF,the impurity Tenofovir isoproxil monoester is less than 1.00%. Also, thetotal impurities are less than 2.0%.

It is to be understood that the present invention is susceptible tomodifications, changes and adaptation by those skilled in the art. Suchmodifications changes and adaptations are intended to be within thescope of the present invention.

We claim:
 1. A process for preparing a granular composition consistingessentially of Tenofovir devoid of an excipient and with content oftotal impurities not more than 2.0% in twin screw processor comprisingthe steps of: a. feeding Tenofovir into the intake zone of the twinscrew processor; b. conveying Tenofovir towards the kneading zone andprocessing it in the kneading zone; c. conveying Tenofovir from thekneading zone towards the exit; d. collecting the Tenofovir granules. 2.The process for preparing granular composition of Tenofovir as claimedin claim 1 wherein the temperature of the barrel in the twin screwprocessor is between 25° C. and 60° C.
 3. The process for preparinggranular composition of Tenofovir as claimed in claim 2 wherein thecontent of Tenofovir isoproxil monoester is not more than 1%; andwherein the content of Tenofovir disoproxil dimer is not more than0.15%.
 4. The process for preparing granular composition of Tenofovir asclaimed in claim 2 wherein the content of adenine is not more than0.15%, the content of Tenofovir isoproxil monoester is not more than 1%,the content of Tenofovir disoproxil ethyl ester is not more than 0.15%,the content of Tenofovir isopropyl isoproxil is not more than 0.3%, thecontent of Tenofovir disoproxil carbamate is not more than 0.15% and thecontent of Tenofovir disoproxil dimer is not more than 0.15%.
 5. Theprocess for preparing granular composition of Tenofovir as claimed inclaim 1 wherein the said composition is stable after storage at 40° C.and 75% Relative Humidity for a period of at least 3 months.
 6. Theprocess for preparing granular composition of Tenofovir as claimed inclaim 1 wherein the said composition is stable after storage at 25° C.and 60% Relative Humidity for a period of at least 3 months.
 7. Theprocess for preparing granular composition of Tenofovir as claimed inclaim 1 wherein the said composition is stable after storage at 2° C. to8° C. for a period of at least 3 months.